Microglia: neuroprotective and neurotrophic cells in the central nervous system

Microglia are currently accepted as sensor cells in the central nervous system that respond to injury and brain disease. The main function of microglia is believed to be brain defense, as they are known to scavenge invading microorganisms and dead cells, and also to act as immune or immunoeffector cells. However, microglia are also thought to contribute to the onset of or to exacerbate neuronal degeneration and/or inflammation in many brain diseases by producing deleterious factors including superoxide anions, nitric oxide and inflammatory cytokines. Nonetheless, microglia have also been shown to act neuroprotectively by eliminating excess excitotoxins in the extracellular space. Moreover, there is accumulating evidence that microglia produce neurotrophic and/or neuroprotective molecules; in particular, it has been suggested that they promote neuronal survival in cases of brain injury. In general, the question of whether microglia act as neurotoxic cells or as neuroprotective cells in vivo has gained much recent attention. In this paper, we provide a review of findings indicating that the microglia are basically neurotrophic/neuroprotective cells in the nervous system. In addition, the mechanism by which neurotrophic microglia become oriented to a neurotoxic state is discussed.     

The role of galanin as a multi-functional neuropeptide in the nervous system.

The neuropeptide galanin is expressed developmentally in the DRG and is rapidly up-regulated 120-fold after peripheral nerve section in the adult. The generation and study of galanin knockout mice has indicated that the peptide is critical to the development and function of specific subsets of neurons in the central and peripheral nervous system. These data have important implications for the understanding, and potential therapeutic treatment, of sensory neuropathies and a number of neurological diseases, including Alzheimer's disease and epilepsy.     

The therapeutic potential of neuropeptide Y in central nervous system disorders with special reference to pain and sympathetically maintained pain

Neuropeptide Y (NPY), a widely distributed peptide, has been shown to have numerous effects in both the central and peripheral nervous systems. In particular, NPY has an important role in mediating analgesia and hyperalgesia by distinct central and peripheral mechanisms. At least six NPY receptor subtypes are known to exist and the development of subtype-specific ligands targeted at NPY receptors will offer novel therapeutic agents. This article will review the involvement of NPY in diverse pathologies of the nervous system, including pain, and will propose a role for NPY in the maintenance of sympathetically maintained pain.     

The role of neuropeptide Y in cardiovascular regulation

Neuropeptide Y (NPY) is a 36 amino acid peptide present in the brain, the adrenal medulla and peripheral sympathetic nerves. The localization and mode of release of NPY led to the proposal that this peptide plays an important role in modulating the contribution of the sympathetic nervous system to blood pressure control. In this paper Bernard Waeber and colleagues review the current knowledge about the mechanisms involved in NPY signal transduction and the different mechanisms whereby NPY, released by the peripheral nervous system, may influence vascular tone and cardiac function.     

The role of neuropeptide Y in energy homeostasis

When administered into the brain, NPY acts at Y1 and Y5 receptors to increase food intake. The response occurs with a short latency and is quite robust, such that exogenous NPY is generally considered to be the most potent of a growing list of orexigenic compounds that act in the brain. The role of endogenous NPY is not so straightforward, however. Evidence from diverse types of experiments suggests that rather than initiating behavioral eating per se, endogenous NPY elicits autonomic responses that prepare the individual to better cope with consuming a calorically large meal.     

雌激素受体在中枢神经系统疾病中的作用

雌激素受体包括核受体和膜受体,分别通过基因组和非基因组效应来发挥转录调控功能。雌激素受体在大脑的皮层、海马、杏仁核和下丘脑中均有表达,发挥着与突触可塑性,学习记忆,认知和神经保护有关的作用。本文就雌激素受体的结构,分类以及在包括阿尔兹海默病,帕金森病,精神分裂症和脑缺血在内的多种中枢神经系统疾病中的作用作一综述。     

Potential neuroprotective role of astroglial exosomes against smoking-induced oxidative stress and HIV-1 replication in the central nervous system

Introduction: HIV-1-infected smokers are at risk of oxidative damage to neuronal cells in the central nervous system by both HIV-1 and cigarette smoke. Since neurons have a weak antioxidant defense system, they mostly depend on glial cells, particularly astrocytes, for protection against oxidative damage and neurotoxicity. Astrocytes augment the neuronal antioxidant system by supplying cysteine-containing products for glutathione synthesis, antioxidant enzymes such as SOD and catalase, glucose for antioxidant regeneration via the pentose-phosphate pathway, and by recycling of ascorbic acid.

Areas covered: The transport of antioxidants and energy substrates from astrocytes to neurons could possibly occur via extracellular nanovesicles called exosomes. This review highlights the neuroprotective potential of exosomes derived from astrocytes against smoking-induced oxidative stress, HIV-1 replication, and subsequent neurotoxicity observed in HIV-1-positive smokers.

Expert opinion: During stress conditions, the antioxidants released from astrocytes either via extracellular fluid or exosomes to neurons may not be sufficient to provide neuroprotection. Therefore, we put forward a novel strategy to combat oxidative stress in the central nervous system, using synthetically developed exosomes loaded with antioxidants such as glutathione and the anti-aging protein Klotho.     

The role of glial monoamine transporters in the central nervous system]

Monoamine transport systems play a very important role in determining the concentrations of monoamines in the synaptic cleft, and therefore the magnitude and duration of the effects of transmitters. Several transport systems for monoamines have been described. The first to be recognized were uptake, a Na(+)-dependent, high-affinity, cocaine-sensitive neuronal transporter, which includes dopamine transporter, norepinephrine transporter and serotonin transporter, and uptake1, a Na(+)-independent, low-affinity, high-capacity, steroid-sensitive extraneuronal transporter. Recently, molecular identification of the uptake2 transporter has been reported, and this has been called extraneuronal monoamine transporter in humans, and organic cation transporter3 in rats. Astrocytes contain these two transport systems that can remove monoamine neurotransmitters from the synaptic cleft by transporters present in the plasma membrane. Since monoamine oxidase and catechol-O-methyl-transferase are present in astroglial cells, their glial uptake systems are likely to play an important role in regulating extracellular monoamine concentrations. This uptake system may be characterized as a second line of defense that inactivates monoamines that have escaped neuronal re-uptake, and thus prevents uncontrolled spreading of the signal. In this review, the identification of monoamine transporters in astrocytes is described and the physiological role of glial monoamine transporters in monoaminergic neurotransmission is discussed.     

BMPs在中枢神经系统发育和神经保护中的作用

骨形态发生蛋白(Bone morphogenetic proteins,BMPs)是转化生长因子-β(transforming growth factor-β)超家族的成员,现已经发现BMPs很多亚型BMP分子在神经系统的不同区域呈持续性表达,但是表达在空间和时间具有差异性,提示不同亚型BMPs的功能在神经系统也存在差异。本文主要就BMPs在中枢神经系统发育中的作用和神经保护功能作一综述。     

Drug transport in the central nervous system: role of carriers

The rate of entry into and distribution of many drugs in the mammalian brain cannot be explained by the physicochemical characteristics of these drugs taking into account the anatomy of the blood-brain barrier. Rather, specialized mechanisms (carriers) in the central nervous system have been sought after and characterized. These carriers explain the observed pharmacokinetic behavior of many drugs in brain. This review summarizes these data in the context of the blood-brain barrier and focuses on several broad principles and selected examples.     

The glutamatergic neurotransmission in the central nervous system

Glutamate is one of the major neurotrasmitters in mammalian brain and changes in its concentration have been associated with a number of neurological disorders, including neurodegenerative, cerebrovascular diseases and epilepsy. Moreover, recently a possible role for glutamatergic system dysfunction has been suggested also in the peripheral nervous system. This chapter will revise the current knowledge in the distribution of glutamate and of its receptors and transporters in the central nervous system.     

Potential role of CYP2D6 in the central nervous system

Abstract

1. Cytochrome P450 2D6 (CYP2D6) is a pivotal enzyme responsible for a major drug oxidation polymorphism in human populations. Distribution of CYP2D6 in brain and its role in serotonin metabolism suggest that CYP2D6 may have a function in the central nervous system.

2. To establish an efficient and accurate platform for the study of CYP2D6 in vivo, a human CYP2D6 (Tg-2D6) model was generated by transgenesis in wild-type (WT) C57BL/6 mice using a P1 phage artificial chromosome clone containing the complete human CYP2D locus, including the CYP2D6 gene and 5′- and 3′-flanking sequences.

3. Human CYP2D6 was expressed not only in the liver but also in the brain. The abundance of serotonin and 5-hydroxyindoleacetic acid in brain of Tg-2D6 is higher than in WT mice, either basal levels or after harmaline induction. Metabolomics of brain homogenate and cerebrospinal fluid revealed a significant up-regulation of L-carnitine, acetyl-L-carnitine, pantothenic acid, 2′-deoxycytidine diphosphate (dCDP), anandamide, N-acetylglucosaminylamine and a down-regulation of stearoyl-L-carnitine in Tg-2D6 mice compared with WT mice. Anxiety tests indicate Tg-2D6 mice have a higher capability to adapt to anxiety.

4. Overall, these findings indicate that the Tg-2D6 mouse model may serve as a valuable in vivo tool to determine CYP2D6-involved neurophysiological metabolism and function.     

Evaluating the role of Toll-like receptors in diseases of the central nervous system

A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll-like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses and are also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain.     

Effects of neuropeptide Y on the cardiovascular system

The actions of neuropeptide Y (NPY) on the circulation is currently the subject of much research that has been stimulated by findings of its co-storage and co-operation with noradrenaline in sympathetic nerve fibres. Lars Edvinsson and colleagues describe the evidence that NPY is involved in the regulation of the cardiovascular system as a neuromodulator/neurotransmitter. This may open novel avenues for the treatment of, for example, hypertension and vasospastic disorders.